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Original article
SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort
  1. Camille Tlemsani1,2,
  2. Armelle Luscan1,2,
  3. Nicolas Leulliot3,
  4. Eric Bieth4,
  5. Alexandra Afenjar5,
  6. Geneviève Baujat6,
  7. Martine Doco-Fenzy7,
  8. Alice Goldenberg8,
  9. Didier Lacombe9,
  10. Laetitia Lambert10,
  11. Sylvie Odent11,
  12. Jérôme Pasche12,
  13. Sabine Sigaudy13,
  14. Alexandre Buffet14,
  15. Céline Violle-Poirsier15,
  16. Audrey Briand-Suleau1,
  17. Ingrid Laurendeau2,
  18. Magali Chin2,
  19. Pascale Saugier-Veber8,16,
  20. Dominique Vidaud1,2,
  21. Valérie Cormier-Daire5,
  22. Michel Vidaud1,2,
  23. Eric Pasmant1,2,
  24. Lydie Burglen5,17
  1. 1Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP, Paris, France
  2. 2EA7331, Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
  3. 3Faculté de Pharmacie, Laboratoire de Cristallographie et RMN Biologiques-CNRS UMR-8015, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
  4. 4Service de Génétique, Hôpital Purpan, Toulouse, France
  5. 5Département de Génétique, Centre de référence des anomalies du développement et syndromes malformatifs, Hôpital Trousseau, AP-HP, Paris, France
  6. 6INSERM UMR_1163, Département de Génétique, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  7. 7Service de génétique HMB CHU Reims, EA 3801, SFR CAPSANTE, Reims, France
  8. 8Service de Génétique, Centre Normand de Génomique Médicale et Médecine personnalisée, CHU de Rouen, Rouen, France
  9. 9Service de Génétique, CHU Bordeaux, Bordeaux, France
  10. 10Service de Génétique, CHU, Nancy, France
  11. 11Service de Génétique, CHU, Rennes, France
  12. 12Service de Pédiatrie, Centre Hospitalier de Polynésie française, Papeete, Tahiti, France
  13. 13Service de Génétique, CHU de Marseille—Hôpital de la Timone, Marseille, France
  14. 14Service d'Endocrinologie, Maladies Métaboliques, Nutrition, Hôpital Larrey, Toulouse, France
  15. 15Département de Génétique, CHU de Reims, Reims, France
  16. 16Inserm U1079, Université de Rouen, IRIB, Rouen, France
  17. 17INSERM UMR_1141, Paris, France
  1. Correspondence to Dr Eric Pasmant, Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, AP-HP, Bâtiment Jean DAUSSET—3ème étage, 27 rue du Faubourg Saint Jacques, Paris, France; eric.pasmant{at}


Background Heterozygous NSD1 mutations were identified in 60%–90% of patients with Sotos syndrome. Recently, mutations of the SETD2 and DNMT3A genes were identified in patients exhibiting only some Sotos syndrome features. Both NSD1 and SETD2 genes encode epigenetic ‘writer’ proteins that catalyse methylation of histone 3 lysine 36 (H3K36me). The DNMT3A gene encodes an epigenetic ‘reader’ protein of the H3K36me chromatin mark.

Methods We aimed at confirming the implication of DNMT3A and SETD2 mutations in an overgrowth phenotype, through a comprehensive targeted-next generation sequencing (NGS) screening in 210 well-phenotyped index cases with a Sotos-like phenotype and no NSD1 mutation, from a French cohort.

Results Six unreported heterozygous likely pathogenic variants in DNMT3A were identified in seven patients: two nonsense variants and four de novo missense variants. One de novo unreported heterozygous frameshift variant was identified in SETD2 in one patient. All the four DNMT3A missense variants affected DNMT3A functional domains, suggesting a potential deleterious impact. DNMT3A-mutated index cases shared similar clinical features including overgrowth phenotype characterised by postnatal tall stature (≥+2SD), macrocephaly (≥+2SD), overweight or obesity at older age, intellectual deficiency and minor facial features. The phenotype associated with SETD2 mutations remains to be described more precisely. The p.Arg882Cys missense de novo constitutional DNMT3A variant found in two patients is the most frequent DNMT3A somatic mutation in acute leukaemia.

Conclusions Our results illustrate the power of targeted NGS to identify rare disease-causing variants. These observations provided evidence for a unifying mechanism (disruption of apposition and reading of the epigenetic chromatin mark H3K36me) that causes an overgrowth syndrome phenotype. Further studies are needed in order to assess the role of SETD2 and DNMT3A in intellectual deficiency without overgrowth.

  • Overgrowth
  • Sotos syndrome
  • SETD2
  • DNMT3A
  • H3K36me3

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  • Contributors All authors of this manuscript fulfil the criteria of authorship. EB, AA, GB, MD-F, AG, DL, LL, SO, JP, SS, AB, PS-V, LB, CV-P and VC-D recruited patients and collected clinical information. NL performed protein structure analysis. IL, AL, CT, DV, AB-S and MC performed sequencing and NGS data analysis. LB, CT, MV and EP designed the study and wrote the manuscript.

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval Local Institutional (Hospital) Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.